Neonatal Herpes Simplex Virus Infection

Neonatal herpes simplex virus infection is a serious, potentially life-threatening infection. It is acquired most commonly by vertical transmission during vaginal delivery from a mother with active genital herpes simplex virus infection. Rarely it is acquired in utero, or postnatally through direct contact with an active herpetic lesion on a caregiver.

There are three clinical patterns: skin-eye-mouth disease, central nervous system disease, and disseminated disease. Severity and prognosis differ substantially between them.

Early presentation is frequently non-specific and sepsis-like, so keep a high index of suspicion in any unwell neonate. Start empirical intravenous aciclovir promptly while diagnostic confirmation is pending, because treatment delay is directly related to significantly worse outcome.

Pathophysiology and transmission risk

• The risk of neonatal transmission is substantially higher with primary maternal genital herpes acquired late in pregnancy, particularly in the final weeks before delivery. There is not enough time for maternal antibody to develop and cross the placenta before delivery.
• With recurrent maternal genital herpes, established maternal immunity substantially reduces transmission risk, though it does not eliminate it.
• Herpes simplex virus type 2 accounts for the majority of neonatal herpes infections. Type 1, from genital and orolabial maternal or caregiver sources, accounts for an increasing proportion in many contemporary settings.
• Disseminated disease reflects haematogenous viral spread affecting multiple organ systems, particularly the liver, lungs and, frequently, the central nervous system. It is the most severe pattern, with the highest mortality even with prompt, appropriate treatment.
• Central nervous system disease, in isolation or as part of disseminated disease, carries a substantial risk of long-term neurological morbidity among survivors even with prompt treatment.

• Skin-eye-mouth disease is the mildest pattern. It presents with vesicular skin lesions and, where present, conjunctivitis or oral mucosal lesions, typically within the first one to two weeks of life.
• This apparently localised presentation carries a substantial risk of progression to disseminated or central nervous system disease if not promptly and adequately treated. It therefore needs the same urgent, full evaluation and treatment as the more severe patterns.
• Central nervous system disease presents with lethargy, poor feeding, temperature instability and seizures. It typically presents somewhat later than skin-eye-mouth disease, generally within the second to third week of life.
• A substantial proportion of affected infants have characteristic cerebrospinal fluid abnormalities and, on neuroimaging, features consistent with herpes simplex encephalitis.
• Disseminated disease presents with a severe, sepsis-like picture, including respiratory distress and hepatic dysfunction (including coagulopathy, reflecting significant hepatic involvement). Concurrent central nervous system involvement is frequent.
• It typically presents within the first one to two weeks of life and is the most severe, rapidly progressive and highest-mortality pattern.
• The substantial majority of infants who develop neonatal herpes simplex virus infection are born to mothers with no recognised history of genital herpes. Maternal infection is frequently unrecognised, asymptomatic or atypical.
• Never use the absence of a known maternal herpes history to reassure against this diagnosis in an unwell neonate with a compatible presentation.

• A high index of suspicion is the essential foundation of prompt diagnosis. Maintain it in any neonate with an unexplained, sepsis-like picture, particularly with vesicular skin lesions, seizures, or hepatic dysfunction with coagulopathy.
• Early presentation is frequently non-specific and overlaps substantially with bacterial neonatal sepsis.
• Polymerase chain reaction testing for herpes simplex virus is the standard, essential diagnostic approach. Test samples from any visible skin, eye or mouth lesion, together with blood and cerebrospinal fluid.
• Sample all relevant, accessible sites in every case of suspected neonatal herpes simplex virus infection, to maximise diagnostic sensitivity.
• Liver function tests, coagulation studies and assessment for disseminated organ involvement are essential parts of the evaluation.
• Examine the cerebrospinal fluid (cell count, protein and glucose, alongside polymerase chain reaction testing), and arrange neuroimaging where central nervous system involvement is a concern.
• Treatment delay is directly related to worse outcome. Start empirical intravenous aciclovir promptly in any neonate whose presentation raises genuine suspicion, without waiting for test results.
• Continue, modify or discontinue treatment according to the eventual diagnostic results and clinical course.

• High-dose intravenous aciclovir, typically 20 mg per kg every eight hours, is the essential, standard treatment. This is a substantially higher weight-based dose than that used for other herpes simplex virus indications, and is needed for adequate efficacy in severe neonatal disease.
• Continue treatment for a minimum of fourteen days for skin-eye-mouth disease and a minimum of twenty-one days for central nervous system or disseminated disease.
• Monitor renal function throughout treatment, because aciclovir-related nephrotoxicity is a recognised risk, particularly at this higher dose.
• In infants with confirmed central nervous system involvement, repeat the cerebrospinal fluid examination toward the end of the planned course. This is generally recommended to confirm clearance of detectable virus before stopping treatment. Extend treatment where viral clearance has not been achieved by the planned endpoint.
• Provide full supportive care in an appropriately resourced neonatal intensive care setting. Address the complications of the pattern present: seizure management for central nervous system disease, and management of coagulopathy and hepatic dysfunction for disseminated disease.
• Give suppressive oral aciclovir for a defined period, generally around six months, after completing the initial intravenous course. It is recommended for infants with confirmed neonatal herpes simplex virus infection of any pattern, because it is shown to improve neurodevelopmental outcome.
• Provide structured, long-term neurodevelopmental follow-up, given the substantial risk of long-term neurological morbidity, particularly after central nervous system or disseminated disease. Add ophthalmological follow-up where relevant to the pattern of disease.
• Prognosis is directly and substantially related to the pattern of disease and, critically, to the promptness of diagnosis and treatment. Maintain a high index of suspicion and a low threshold for empirical treatment in any neonate with a compatible presentation.